Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis
Yasser Iturria‐Medina(Montreal Neurological Institute and Hospital), Roberto C. Sotero(University of Calgary), P.-J. Toussaint(Montreal Neurological Institute and Hospital), J.M. Mateos-Pérez(Montreal Neurological Institute and Hospital), Alan C. Evans(Montreal Neurological Institute and Hospital), The Alzheimer’s Disease Neuroimaging Initiative(University of California, San Francisco), Michael W. Weiner(UC San Diego Health System), Paul Aisen(Mayo Clinic), Ronald C. Petersen(Mayo Clinic), Clifford R. Jack(University of California, Berkeley), William J. Jagust(University of Pennsylvania), John Q. Trojanowki(LAC+USC Medical Center), Arthur W. Toga(University of California, Davis), Laurel Beckett(Brigham and Women's Hospital), Robert C. Green(Indiana University Bloomington), Andrew J. Saykin(Washington University in St. Louis), John C. Morris(University of Pennsylvania), Leslie M. Shaw(UC San Diego Health System), Zaven S. Khachaturian(Siemens (Germany)), Greg Sorensen(Pittsburg State University), Lew Kuller(Washington University in St. Louis), Marc Raichle(Cornell University), Steven M. Paul(Albert Einstein College of Medicine), Peter Davies(Alzheimer's Drug Discovery Foundation), Howard Fillit(Acumen Pharmaceuticals (United States)), Franz Hefti(Washington University in St. Louis), Davie Holtzman(Northwestern University), M. Marcel Mesulam(National Institute of Mental Health), William Z. Potter(Brown University), Peter J. Snyder(Eli Lilly (United States)), Adam J. Schwartz(University of Washington), Tom Montine(UC San Diego Health System), Ronald G. Thomas(UC San Diego Health System), Michael Donohue(UC San Diego Health System), Sarah Walter(UC San Diego Health System), Devon Gessert(UC San Diego Health System), Tamie Sather(UC San Diego Health System), Gus Jiminez(University of California, Davis), Danielle Harvey(Mayo Clinic), Matt A. Bernstein(Universidad de Londres), Nick C. Fox(UCLA Health), Paul M. Thompson(University of California, San Francisco), Norbert Schuff(Mayo Clinic), Bret Borowski(Mayo Clinic), Jeff Gunter(Mayo Clinic), Matthew L. Senjem(Mayo Clinic), Prashanthi Vemuri(Mayo Clinic), David T. Jones(Mayo Clinic), Kejal Kantarci(Mayo Clinic), Chad Ward(University of Michigan), Robert A. Koeppe(University of Utah), Norm Foster(Alzheimer's Association), Eric M. Reiman(Alzheimer's Association), Kewei Chen(Pittsburg State University), Chet Mathis(University of California, Berkeley), Susan Landau(Washington University in St. Louis), Nigel J. Cairns(Washington University in St. Louis), Erin Householder(Washington University in St. Louis), Lisa Taylor‐Reinwald(University of Pennsylvania), Virginia Lee(University of Pennsylvania), Magdalena Korecka(University of Pennsylvania), Michal Figurski(LAC+USC Medical Center), Karen Crawford(LAC+USC Medical Center), Scott Neu(Indiana University Bloomington), Tatiana Foroud(University of Michigan), Steven Potkin(Indiana University Bloomington), Li Shen(Indiana University Bloomington), Kelley Faber(Indiana University Bloomington), Sungeun Kim(Indiana University Bloomington), Kwangsik Nho(UC San Diego Health System), Leon J. Thal(National Institute on Aging), Neil Buckholtz(Johns Hopkins University), Marylyn Albert, Richard Frank(National Institute on Aging), John Hsiao(Oregon Health & Science University), Jeffrey Kaye(Oregon Health & Science University), Joseph F. Quinn(Oregon Health & Science University), Betty Lind(Oregon Health & Science University), Raina Carter(Oregon Health & Science University), Sara Dolen(LAC+USC Medical Center), Lon S. Schneider(LAC+USC Medical Center), Sonia Pawluczyk(LAC+USC Medical Center), Mauricio Beccera(LAC+USC Medical Center), Liberty Teodoro(LAC+USC Medical Center), Bryan M. Spann(UC San Diego Health System), James B. Brewer(UC San Diego Health System), Helen Vanderswag(Alzheimer's Association), Adam Fleisher(University of Michigan), Judith L. Heidebrink(University of Michigan), Joanne Lord(Mayo Clinic), Sara S. Mason(Mayo Clinic), Colleen S. Albers(Mayo Clinic), David S. Knopman(Mayo Clinic), Kris Johnson(Baylor College of Medicine), Rachelle S. Doody(Baylor College of Medicine), Javier Villanueva‐Meyer(Baylor College of Medicine), Munir Chowdhury(Baylor College of Medicine), Susan Rountree(Baylor College of Medicine), Mimi Dang(Baylor College of Medicine), Yaakov Stern(Baylor College of Medicine), Lawrence S. Honig(Baylor College of Medicine), Karen L. Bell(Washington University in St. Louis), Beau M. Ances(Washington University in St. Louis), Maria Carroll(Washington University in St. Louis), Sue Leon(Washington University in St. Louis), Mark A. Mintun(Washington University in St. Louis), Stacy Schneider(Washington University in St. Louis), Angela Oliver(University of Alabama at Birmingham), Daniel Marson(University of Alabama at Birmingham), Randall Griffith(University of Alabama at Birmingham), David Clark(University of Alabama at Birmingham), David Geldmacher(University of Alabama at Birmingham), John Brockington(University of Alabama at Birmingham), Erik D. Roberson(Icahn School of Medicine at Mount Sinai), Hillel Grossman(Icahn School of Medicine at Mount Sinai), Effie Mitsis(Rush University Medical Center), Leyla de Toledo‐Morrell(Rush University Medical Center), Raj C. Shah, Ranjan Duara, Daniel Varón, Maria T. Greig, Peggy Roberts(Johns Hopkins University), Marilyn Albert(Johns Hopkins University), Chiadi U. Onyike(Johns Hopkins University), Daniel D’Agostino(Johns Hopkins University), Stephanie Kielb(New York University), James E. Galvin(New York University), Brittany Cerbone(New York University), Christina A. Michel(New York University), Henry Rusinek(New York University), Mony J. de Leon(New York University), Lidia Glodzik(New York University), Susan De Santi(Duke Medical Center), P. Murali Doraiswamy(Duke Medical Center), Jeffrey R. Petrella(Duke Medical Center), Terence Z. Wong(University of Pennsylvania), Steven E. Arnold(University of Pennsylvania), Jason Karlawish(University of Pennsylvania), David A. Wolk(University of Kentucky), Charles D. Smith(University of Kentucky), Gregory A. Jicha(University of Kentucky), Peter Hardy(University of Kentucky), Partha Sinha(University of Kentucky), Elizabeth Oates(University of Kentucky), Gary Conrad(Pittsburg State University), Oscar L. López(Pittsburg State University), MaryAnn Oakley(Johns Hopkins University), Donna M. Simpson(University of Rochester Medical Center), Anton P. Porsteinsson(University of Rochester Medical Center), Bonnie S. Goldstein(University of Rochester Medical Center), Kim Martin(University of Rochester Medical Center), Kelly M. Makino(University of Rochester Medical Center), M. Saleem Ismail(University of Rochester Medical Center), Connie Brand(UC Irvine Health), Ruth A. Mulnard(UC Irvine Health), Gaby Thai(UC Irvine Health), Catherine Mc-Adams-Ortiz(The University of Texas Southwestern Medical Center), Kyle Womack(The University of Texas Southwestern Medical Center), Dana Mathews(The University of Texas Southwestern Medical Center), Mary Quiceno(The University of Texas Southwestern Medical Center), Ramon Diaz‐Arrastia(The University of Texas Southwestern Medical Center), Richard King(The University of Texas Southwestern Medical Center), Myron Weiner(The University of Texas Southwestern Medical Center), Kristen Martin-Cook(The University of Texas Southwestern Medical Center), Michael D. Devous(Emory University), Allan I. Levey(Emory University), James J. Lah(Emory University), Janet S. Cellar(University of Kansas Medical Center), Jeffrey M. Burns(University of Kansas Medical Center), Heather S. Anderson(University of Kansas Medical Center), Russell H. Swerdlow(UCLA Health), Liana G. Apostolova(UCLA Health), Kathleen Tingus(UCLA Health), Ellen Woo(UCLA Health), Daniel Silverman(UCLA Health), Po H. Lu(UCLA Health), George Bartzokis(Jacksonville College), Neill R. Graff‐Radford(Jacksonville College), Francine Parfitt(Jacksonville College), Tracy Kendall(Jacksonville College), Heather Johnson(Indiana University Bloomington), Martin R. Farlow(Indiana University Bloomington), AnnMarie Hake(Indiana University Bloomington), Brandy R. Matthews(Indiana University Bloomington), Scott Herring(Indiana University Bloomington), Cynthia Hunt(Yale University), Christopher H. van Dyck(Yale University), Richard E. Carson(Yale University), Martha G. MacAvoy(Jewish General Hospital), Howard Chertkow(Jewish General Hospital), Howard Bergman(Jewish General Hospital), Chris Hosein(Sunnybrook Health Science Centre), Sandra E. Black(Sunnybrook Health Science Centre), Bojana Stefanovic(Sunnybrook Health Science Centre), Curtis Caldwell, Ging‐Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly(Cleveland Clinic), Andrew Kertesz(St Joseph's Health Centre), John Rogers(St Joseph's Health Centre), Charles Bernick(St Joseph's Health Centre), Donna Munic(Northwestern University), Diana Kerwin(Northwestern University), Marek-Marsel Mesulam(Northwestern University), Kristine Lipowski(Northwestern University), Chuang-Kuo Wu(Northwestern University), Nancy Johnson(Palm Beach Neurology), Carl Sadowsky(Palm Beach Neurology), Walter Martínez(Palm Beach Neurology), Teresa Villena(Georgetown University), Raymond Scott Turner(Georgetown University), Kathleen Johnson(Georgetown University), Brigid Reynolds(Brigham and Women's Hospital), Reisa A. Sperling(Brigham and Women's Hospital), Keith A. Johnson(Brigham and Women's Hospital), Gad A. Marshall(Brigham and Women's Hospital), Meghan Frey(Brigham and Women's Hospital), Barton Lane(Brigham and Women's Hospital), Allyson Rosen(Brigham and Women's Hospital), Jared Tinklenberg(Banner Sun Health Research Institute), Marwan N. Sabbagh(Banner Sun Health Research Institute), Christine M. Belden(Banner Sun Health Research Institute), Sandra A. Jacobson(Banner Sun Health Research Institute), Sherye A. Sirrel(Boston University), Neil W. Kowall(Boston University), Ronald Killiany(Boston University), Andrew E. Budson(Boston University), Alexander Norbash(Boston University), Patricia Lynn Johnson(Howard University), Joanne Allard(Case Western Reserve University), Alan J. Lerner(Case Western Reserve University), Paula Ogrocki(Case Western Reserve University), Leon Hudson(University of California, Davis), Evan Fletcher(University of California, Davis), Owen Carmichael(University of California, Davis), John Olichney(University of California, Davis), Charles DeCarli(Neurological Surgery), Smita Kittur, Michael Borrie, T-Y Lee, Robert Bartha(University of Wisconsin–Madison), Sterling C. Johnson(University of Wisconsin–Madison), Sanjay Asthana(University of Wisconsin–Madison), Cynthia M. Carlsson(University of Michigan), Steven G. Potkin(University of Michigan), Adrian Preda(University of Michigan), Dana Nguyen(Alzheimer's Association), Pierre N. Tariot(Alzheimer's Association), Stephanie Reeder(Dent Neurologic Institute), Vernice Bates(Dent Neurologic Institute), Horacio Capote(Dent Neurologic Institute), Michelle Rainka(The Ohio State University), Douglas W. Scharre(The Ohio State University), Maria Kataki(The Ohio State University), Anahita Adeli(Albany Medical Center Hospital), Earl A. Zimmerman(Albany Medical Center Hospital), Dzintra Celmins(Albany Medical Center Hospital), Alice D. Brown(Hartford Hospital), Godfrey D. Pearlson(Hartford Hospital), Karen Blank(Hartford Hospital), Karen Anderson(Dartmouth–Hitchcock Medical Center), Robert B. Santulli(Dartmouth–Hitchcock Medical Center), Tamar J. Kitzmiller(Dartmouth–Hitchcock Medical Center), Eben S. Schwartz(Wake Forest University), Kaycee M. Sink(Wake Forest University), Jeff D. Williamson(Wake Forest University), Pradeep Garg(Wake Forest University), Franklin Watkins(Rhode Island Hospital), Brian R. Ott(Rhode Island Hospital), Henry Querfurth(Rhode Island Hospital), Geoffrey Tremont(Providence College), Stephen Salloway(Providence College), Paul Malloy(Providence College), Stephen Correia(University of California, San Francisco), Howard J. Rosen(University of California, San Francisco), Bruce L. Miller(Medical University of South Carolina), Jacobo Mintzer(Medical University of South Carolina), Kenneth Spicer(Medical University of South Carolina), David Bachman(St Joseph's Health Care), Elizabeth Finger(St Joseph's Health Care), Stephen Pasternak(St Joseph's Health Care), Irina Rachinsky(St Joseph's Health Care), Dick Drost(Nathan Kline Institute for Psychiatric Research), Nunzio Pomara(Nathan Kline Institute for Psychiatric Research), Raymundo Hernando(Nathan Kline Institute for Psychiatric Research), Antero Sarrael(University of Iowa), Susan K. Schultz(University of Iowa), Laura L. Boles Ponto(University of Iowa), Hyungsub Shim(University of Iowa), Karen E. Smith(Cornell University), Norman Relkin(Cornell University), Gloria Chaing(Cornell University), Lisa Raudin(University of South Florida), Amanda Smith(University of South Florida), Kristin Fargher(University of South Florida), Balebail Ashok Raj(University of California, San Francisco), Thomas C. Neylan(Northwestern University), Jordan Grafman(UC San Diego Health System), Melissa Davis(UC San Diego Health System), Rosemary Morrison(University of California, San Francisco), Jacqueline Hayes(University of California, San Francisco), Shannon Finley(United States Department of Defense), Karl E. Friedl(Rush University Medical Center), Debra Fleischman(Rush University Medical Center), Konstantinos Arfanakis(Duke Medical Center), Olga James(Medical University of South Carolina), Dino Massoglia(University of Wisconsin–Madison), J. Jay Fruehling(University of Wisconsin–Madison), Sandra Harding(University of Washington), Elaine R. Peskind(The Ohio State University), Eric C. Petrie(The Ohio State University), Gail Li(Stanford University), Jerome A. Yesavage(Stanford University), Joy L. Taylor(Stanford University), Ansgar J. Furst
Cited by 1,187Open Access
Abstract
Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
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